Loss of neurons by a degenerative process is a pathological feature of many human neurological disorders. Neuronal cell death is a normal part of tissue development and maintenance. Abnormal neuronal cell death, however, occurs as a result of a variety of conditions including, but not limited to, traumatic injury or trauma, ischemia, and neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and stroke.
Spinal muscular atrophy (SMA) (Roberts, et al. (1970) Arch. Dis. Child. 45:33-38), an autosomal recessive disease with characteristics of motor neuron degeneration and muscle atrophy, is a common childhood genetic disorder and the most frequent genetic cause of infant mortality (Roberts, et al. (1970) ibid.; Pearn, J. (1980) Lancet 1:919-922; Czeizel and Hamula (1989) J. Med. Genet. 26:761-763). Based on the age of onset and the severity of the disease, SMA is classified as severe type I (Werdnig-Hoffman disease), moderate type II, or mild type III (Kugelberg-Welander disease). The survival motor neuron (SMN) gene has been linked to SMA. The human genome contains two copies of the SMN gene because of an inverted duplication at 5q13. This phenomenon appears to be human-specific as all other organisms examined to date have a single copy of SMN. Deletions or mutations of the telomeric SMN1 gene, which result in reduced SMN protein level, have been found in the vast majority of SMA patients (Cobben, et al. (1995) Am. J. Hum. Genet. 57:805-808; Bussaglia, et al. (1995) Nat. Genet. 11:335-337; Hahnen, et al. (1995) Hum. Mol. Genet. 4:1927-1933; Rodrigues, et al. (1995) Hum. Mol. Genet. 4:631-634; Lefebvre, et al. (1995) Cell 80:155-165; Chang, et al. (1995) Am. J. Hum. Genet. 57:1503-1505; Hahnen, et al. (1996) Am. J. Hum. Genet. 59:1057-1065; Velasco, et al. (1996) Hum. Mol. Genet. 5:257-263).
One strategy for the treatment of SMA has been to increase the amount of SMN protein. As SMA patients have a functional centromeric copy of the gene, referred to as smn2, investigations have been conducted to identify compounds that shift the alternative splicing pattern of the SMN2-derived pre-mRNA, which normally primarily produces exon7-deleted non-functional SMN protein, to increase the production of full-length SMN (Chang, et al. (2001) Proc. Natl. Acad. Sci. U.S.A. 98:9808-9813; Andreassi, et al. (2001) Hum. Mol. Genet. 10:2841-2849). To date, the compounds identified in these screens, aclarubicin and butyric acid, are either very toxic or too pleiotropic and carry a very high risk of serious side effects.
Although motor neurons are the only known cell type to be effected in SMA patients, SMN protein is expressed ubiquitously in all tissues and cell types examined (Lefebvre, et al. (1995) Cell 80:155-165; Lefebvre, et al. (1997) Nat. Genet. 16:265-269; Coovert, et al. (1997) Hum. Mol. Genet. 6:1205-1214). SMN is believed to participate in several divergent cellular processes. For example, in addition to its cytoplasmic localization, SMN is also found in a subnuclear structure, referred to as gems, which is found in the vicinity of, and often overlaps with, coiled bodies (Liu, et al. (1997) Cell 90:1013-1021). The function of coiled bodies is unknown. However, they are known to contain spliceosomal small nuclear ribonucleoprotein particles (snRNPs), which function in pre-mRNA splicing, and components of small nucleolar ribonucleoprotein particles, which are involved in pre-rRNA processing. Therefore, coiled bodies have been suggested to play a role or roles in snRNP and small nucleolar ribonucleoprotein particle metabolism (Gall, et al. (1995) Dev. Genet. 16:25-35). Because gems and coiled bodies are often associated and contain similar sets of proteins and RNAs, it is believed that they have related functions. Moreover, SMN has been shown to interact with a group of Sm proteins, the core proteins of snRNPs, and a protein, Gemin2, formerly known as SIP1, both in vitro and in vivo (Liu, et al. (1997) supra). Injection of antibodies against either SMN or Gemin2 into Xenopus oocytes inhibits assembly and import of snRNPs, thus indicating that the SMN-Gemin2 complex performs an important function in snRNP metabolism (Fischer, et al. (1997) Cell 90:1023-1029; Buhler, et al. (1999) Hum. Mol. Genet. 8:2351-2357). A dominant negative mutant of SMN, SMNN27, also inhibits snRNP assembly in the cytoplasm (Pellizzoni, et al. (1998) Cell 95:615-624). Moreover, the nuclear pool of SMN protein was found to be required for pre-mRNA splicing, which may facilitate regeneration or recycling of snRNPs in the nucleus (Pellizzoni, et al. (1998) ibid.). Recently, two additional proteins, Gemin3 and Gemin4, which are associated with SMN, were described (Charroux, et al. (1999) J. Cell Biol. 147:1181-1194; Charroux, et al. (2000) J. Cell Biol. 148:1177-1186). SMN may also be involved in regulation of gene expression by interacting with transcriptional activators (Strasswimmer, et al. (1999) Hum. Mol. Genet. 8:1219-1226; Campbell, et al. (2000) Hum. Mol. Genet. 9:1093-1100; Williams, et al. (2000) FEBS Lett. 470:207-210). The ability of SMN to directly bind RNA, along with its close localization to microtubules in the cytoplasm and neuronal dendrites and axons, indicates that SMN may be involved in the transport of RNA (Lorson and Androphy (1998) Hum. Mol. Genet. 7:1269-1275; Bechade, et al. (1999) Eur. J. Neurosci. 11:293-304; Bertrandy, et al. (1999) Hum. Mol. Genet. 8:775-782; Pagliardini, et al. (2000) Hum. Mol. Genet. 9:47-56). As a means of better defining the function of SMN and for screening for compounds which can substitute for SMN function, Wang and Dreyfuss ((2001) J. Biol. Chem. 276:9599-9605) developed a cell line which is deficient in endogenous SMN and expresses exogenous SMN under the control of a tetracycline-repressible promoter.
Psychiatric disorders are pathological conditions of the brain characterized by identifiable symptoms that result in abnormalities in cognition, emotion or mood, or the highest integrative aspects of behavior. These disorders may vary in severity of symptoms, duration, and functional impairment. Psychiatric disorders afflict millions of people worldwide resulting in tremendous human suffering and economic burden due to lost productivity.
Inappropriate treatment of these diseases seriously compromises the patient's quality of life, causing emotional suffering and increasing the risk of lost livelihood and disrupting social integration. In the most severe cases these disorders can lead to suicide.
Over the past several decades, the use of pharmacological agents to treat psychiatric disorders has greatly increased. The reason for this increase is largely due to research advances in both neuroscience and molecular biology. In addition, compounds have been generated that are more effective therapeutic agents with fewer side effects, targeted to correct the biochemical alterations that accompany mental disorders.
Calmidazolium and W7, potent inhibitors of calmodulin (CaM), protect pyramidal cells in the CA1 region of the hippocampus against hypoxia/hypoglycemia (Sun, et al. (1997) Neuroreport 8:415-418). Furthermore, calmidazolium and KN-93, a Ca2+/CaM-dependent protein kinase II (CaMKII)-specific inhibitor, block long-term depression (Margrie, et al. (1998) Nat. Neurosci. 1:378-383). A number of clinically-effective antipsychotic drugs also bind to calmodulin (Weiss, et al. (1980) Adv. Cyclic Nucleotide Res. 12:213-225).
Despite advances that have occurred from a better understanding of neuropharmacology, however, many neurological and psychiatric diseases remain untreated or inadequately treated with current pharmaceutical agents. Accordingly, there is a need for antineurodegenerative and psychopharmacological agents that are effective in the treatment of neurological and psychiatric disorders.
It has now been found that various compounds typically categorized as an antidepressant, antipsychotic, antihistamine, anticholinergic, antiparkinsonian, neuroleptic, adrenergic blocker, muscle relaxant, vasodilator, antihyperlipoproteinemic, antispasmodic, platelet aggregation inhibitor, oxytocin, antitussive, antipruritic, antiemetic, sedative, hypnotic, respiratory stimulant, or antiserotonin exhibit the ability to replace or enhance the function of SMN. These compounds are thus useful broadly in the treatment of neurodegenerative diseases and disorders. The invention also the invention provides methods and kits for identifying additional compounds and using such compounds in the treatment of neurological and psychiatric diseases and disorders.